DESCRIPTION(Adapted from applicant's abstract): Neuronal activity is a dynamic interplay between excitatory and inhibitory synaptic inputs. Balance between the excitatory and inhibitory systems is essential for functional neuronal circuits. In the CNS, glutamatergic synapses conduct ubiquitous excitatory inputs and GABAergic synapses inhibitory inputs. The classic example of excitatory-inhibitory inbalance is the epileptic seizure where excitatory inputs override inhibitory inputs. Traditionally, two types of excitatory-inhibitory circuits, feedback and feedforward, have been proposed to maintain this balance. However, recent studies suggest that the tissue levels of glutamate also modulate inhibitory synapses. Glutamate around GABAergic synapses may directly control the efficacy of inhibitory transmission. GABAergic synapses are heterogeneous in their properties and functions, and thereby may be differentially modulated by dynamic changes in glutamate levels. In preliminary experiments using dual patch clamp recording techniques in synaptically-coupled pairs of hippocampal interneurons and pyramidal neurons to record unitary inhibitory postsynaptic currents (uIPSCs), we have found that blockade of the glutamate kainate receptor (KAR) by CNQX or the KAR antagonist NS102, but not SYM2206 or GYKI53655, caused an increase in the failure rate of uIPSCs at low-failure GABAergic synapses. By contrast, activation of KARs by low concentrations of agonists decreased the failure rate of uIPSCs at high-failure synapses. On the other hand, high concentrations of KAR agonists induced a depression of uIPSCs at low-failure synapses. We hypothesize that different levels of glutamate differentially modulates GABAergic synapses through activation of KARs. Basal glutamate potentiates inhibitory transmission primarily at low-failure synapses. A mild elevation of glutamate enhances inhibitory transmission predominately at high-failure synapses. Finally, high levels of glutamate depress inhibitory transmission especially at low-failure synapses. Spillover of glutamate from excitatory synapses potentiates high-failure GABAergic synapses and thereby protects neuronal circuits from overwhelming excitation. This application will use unique dual patch-clamp techniques to record uIPSCs, activity of individual GABAergic synapses, to provide new insights into the physiological and pathological roles of KARs in the interplay between excitatory and inhibitory synapses. The KAR-mediated modulation of GABAergic synapses provides a fundamental new mechanism for glutamate-mediated interaction between excitatory and inhibitory synapses.